Cote Samantha R, Kuzhikandathil Eldo V
Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, NJ, USA.
Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, NJ, USA.
Neuropharmacology. 2014 Apr;79:359-67. doi: 10.1016/j.neuropharm.2013.11.023. Epub 2013 Dec 5.
The D3 dopamine receptor has the highest affinity for dopamine, many antipsychotics as well as agonists used to treat Parkinson's disease and related disorders. We and others have reported that the D3 receptor exhibits a tolerance property wherein repeated agonist stimulation of the receptor results in a progressive loss of agonist-induced signaling response. Recently we reported that the D3 receptor tolerance property is agonist dependent and identified a novel agonist, ES609, which does not elicit D3 receptor tolerance. Here, we used the classical tolerance-inducing D3 receptor agonist, PD128907, and the novel agonist, ES609, to demonstrate that the D3 receptor tolerance property is exhibited not only in cellular signaling in vitro and in vivo, but also manifests at the behavior level. Using AtT-20 cells stably expressing D3 receptors we show that PD128907, but not ES609, induces tolerance in the D3 receptor-mitogen activated protein kinase (MAPK) pathway. Using the novel drd3-EGFP reporter mice, we demonstrate that 0.05 mg/kg PD128907 and 10 mg/kg ES609 selectively activate the D3 receptor-MAPK signaling pathway in vivo; however, only PD128907 induces tolerance. Locomotor behavior assessment showed that both PD128907 and ES609 decreased locomotor activity of the drd3-EGFP mice. While the agonist-induced decrease in locomotor activity was attenuated in drd3-EGFP mice administered two sequential doses of tolerance-inducing agonist PD128907, this attenuation was not seen in mice repeatedly administered the novel agonist, ES609. Together the results suggest that the D3 receptor tolerance property is exhibited in MAPK signaling in vitro and in vivo and also affects agonist-induced locomotor behavior.
D3多巴胺受体对多巴胺、许多抗精神病药物以及用于治疗帕金森病和相关疾病的激动剂具有最高亲和力。我们和其他人曾报道，D3受体具有一种耐受特性，即对该受体的重复激动剂刺激会导致激动剂诱导的信号反应逐渐丧失。最近我们报道，D3受体的耐受特性取决于激动剂，并鉴定出一种新型激动剂ES609，它不会引发D3受体耐受。在此，我们使用经典的诱导耐受的D3受体激动剂PD128907和新型激动剂ES609，来证明D3受体的耐受特性不仅在体外和体内细胞信号传导中表现出来，而且在行为水平上也有体现。利用稳定表达D3受体的AtT-20细胞，我们发现PD128907而非ES609会在D3受体-丝裂原活化蛋白激酶（MAPK）途径中诱导耐受。使用新型的drd3-EGFP报告基因小鼠，我们证明0.05 mg/kg的PD128907和10 mg/kg的ES609在体内选择性激活D3受体-MAPK信号通路；然而，只有PD128907会诱导耐受。运动行为评估显示，PD128907和ES609均降低了drd3-EGFP小鼠的运动活性。虽然在给予两剂诱导耐受的激动剂PD128907的drd3-EGFP小鼠中，激动剂诱导的运动活性降低有所减弱，但在反复给予新型激动剂ES609的小鼠中未观察到这种减弱。这些结果共同表明，D3受体的耐受特性在体外和体内的MAPK信号传导中均有体现，并且还会影响激动剂诱导的运动行为。
